Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70

被引：25

作者：

Cheeseman, Matthew D. ^{[1
]}

Westwood, Isaac M. ^{[1
,2
]}

Barbeau, Olivier ^{[1
]}

Rowlands, Martin ^{[1
]}

Dobson, Sarah ^{[1
,2
]}

Jones, Alan M. ^{[1
]}

Jeganathan, Fiona ^{[1
]}

Burke, Rosemary ^{[1
]}

Kadi, Nadia ^{[1
]}

Workman, Paul ^{[1
]}

Collins, Ian ^{[1
]}

van Montfort, Rob L. M. ^{[1
,2
]}

Jones, Keith ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Canc Therapeut Unit, London SW7 3RP, England

[2] Inst Canc Res, Div Struct Biol, London SW7 3RP, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 10期

关键词：

NUCLEOTIDE-BINDING DOMAIN; HEAT-SHOCK PROTEINS; ALLOSTERIC REGULATION; MOLECULAR CHAPERONE; MEDICINAL CHEMISTRY; SALT-BRIDGES; ATPASE ACTIVITY; DRUG TARGETS; HEAT-SHOCK-PROTEIN-70; IDENTIFICATION;

D O I：

10.1021/acs.jmedchem.5b02001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

引用

页码：4625 / 4636

页数：12

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